Tumor uptake of 64Cu-DOTA-trastuzumab correlates with HER2 gene amplification in patients with metastatic breast cancer

49 Objectives Tumor uptake of 64Cu-DOTA-trastuzumab varies widely among patients with human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (Mortimer,et al., JNM 2014; 55:23-29). We sought to determine the degree to which this observation reflects variation of HER2 gene amplification, a strong correlate of tumor HER2 expression (Slamon, et al., Science 1989;244:707-712). Methods PatientHER2 statusat time of studywas determined from biopsied tumor tissue and classified by standard criteria [HER2+: immunohistochemistry IHC 3+ or IHC 2+ and fluorescence in situ hybridization (FISH)-derived HER2-to-reference gene copy ratio > 2.0]. Patients with HER2+ (n=8) or HER2- (n=10) metastatic breast cancer who had not received anti-HER2 therapy for 蠅 2 mo were given trastuzumab i.v. (45 mg, to reduce liver uptake) prior to i.v. injection of 64Cu-DOTA-trastuzumab (364-551 MBq). PET-CT scans were obtained at 21-25 h (3-4 bed positions, 20 or 15 min each) over fields of view based on recent (≤ 17 d prior) 18F-FDG scans. Radiolabel uptake in lesions with maximum diameter on CT 蠅 15 mm (3-10 per patient) was measured as maximum voxel SUV (SUVmax). Residual tissue from tumor biopsies was assayed by FISH to determine average number of HER2 gene copies per tumor cell ( ). Results Intra-patient average SUVmax ( , range 3-16 g/mL) was positively correlated (r = 0.86, P (range 2-28). The HER2+ group had higher average than the HER2- group [9.1 ± 3.8 vs 4.9 ± 1.1 g/mL (mean ± SD); P accounted for more of the variance in than did HER2 class (74 vs 42%). Although the two groups were well separated with respect to , two HER2+ patients had lower than three of the HER2- patients. Furthermore, some HER2+ patients with very similar had widely different , indicating that tumor uptake is not determined solely by HER2 expression. Conclusions Tumor uptake of64Cu-DOTA-trastuzumab reflects binding to HER2 as early as 1 d post injection. Measurement of by FISH is a better predictor of trastuzumab uptake than standard HER2 classification. The wide range of 64Cu-DOTA-trastuzumab uptake among HER2+ patients correlates with variable tumor HER2 expression driven by variations in gene amplification. However, HER2 expression/gene amplification is not the only significant determinant of trastuzumab uptake. RESEARCH SUPPORT. DOD1024511.